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    • We focus here on the historical discoveries that led to

    2022-09-15

    We focus here on the historical discoveries that led to the development of the concept of ferroptosis. Ferroptosis is defined as an iron-dependent form of regulated cell death, which occurs through the lethal accumulation of lipid-based reactive oxygen species (ROS) when glutathione (GSH)-dependent lipid peroxide repair systems are compromised [24]. Ferroptosis involves genetic, metabolic, and protein regulators, triggers, and execution mechanisms that for the most part do not overlap with other forms of regulated cell death [25]. Ferroptotic cell death can be inhibited by lipophilic antioxidants, iron chelators, inhibitors of lipid peroxidation, and depletion of polyunsaturated fatty acyl phospholipids (PUFA-PLs), which are prime substrates driving lethal lipid peroxidation [24], [26].
    Early observations consistent with ferroptosis Ferroptosis has been observed a number of times over the years prior to the detailed molecular understanding of this cell death process, and the concept that it exists (summarized in Fig. 1 and Table 1). Yet, until it was termed as such in 2012, reports describing what we now know as cell death with ferroptotic characteristics were attributed to other cell death mechanisms, or not recognized as being biologically significant. For example, metabolic dependencies leading to cell death were noted in the decades before ferroptosis was discovered: early in the 1950's, studies were performed by Harry Eagle and colleagues to test the requirements for specific metabolites, such as amino acids, vitamins and other nutrients, to support growth and proliferation of mammalian cells in culture [27], [28], [29]. These reports showed that starvation of just a single amino comt inhibitor out of 13 different amino acids tested inhibited the growth of human and mouse cells in culture: cells deprived of cystine exhibited a unique microscopic morphology that was different from the morphologies apparent upon deprivation of other amino acids, which the authors speculated to be similar to death caused by viral infection [28]. In 1959, these investigators found that in cystine-free medium, incorporation of cysteine in de novo protein biosynthesis did not suffice to restore cell growth, thus concluding that cystine entails an additional metabolic function besides incorporation into protein. These studies linked cystine deprivation with the disappearance of glutathione and showed that glutathione supplementation could promote growth in cystine-free media [29], [30]. Presumably, cysteine did not suffice because it is taken up by cells through different mechanisms than cystine. In the early 1970's, there were reports of hepatic necrosis (that today would be referred to as ferroptosis) in mice, which was accompanied by glutathione depletion and could be rescued by pretreatment of glutathione or cysteine [31]. In the 1970's, Shiro Bannai and colleagues showed that cystine starvation led to reduction in cellular glutathione and cell death [32]. Supporting the contribution of reactive oxygen species (ROS) accumulation in the induction of cell death was the investigators’ observation that this cystine-deprivation-induced death could be rescued by the addition of the lipophilic antioxidant α-tocopherol (a component of vitamin E), without restoring glutathione levels [32]. These results implied that cysteine, derived from reduction of cystine, was needed to sustain glutathione levels and to prevent lipid-ROS-based toxicity, which could also be prevented by lipophilic antioxidants. In the following years, several studies confirmed the crucial role of cellular cysteine deprivation and glutathione depletion in inducing cell death, and demonstrated that both iron chelators (or serum-deprivation due to lack of iron) and lipophilic antioxidants could block such death from occurring [33], [34], [35], [36], [37], [38], [39], [40], [41], which are now recognized as the cardinal features of ferroptosis. These common dependencies and features were demonstrated in many types of mammalian cells, including human embryonic fibroblasts [42], hybridomas and myelomas [33], cortical neurons [34], [35], [36], oligodendroglia [37], oligodendrocytes [38], [39] and hair cells [43]. Remarkably, these numerous studies recognized reactive oxygen species as drivers of the death process, as well as several distinct triggers and rescuers of cell death, but were nonetheless not interpreted as evidence for a distinct cell death process that does not overlap with apoptosis or necrosis, although it was speculated upon in some cases (e.g., [44]). The situation is similar to the history of protein degradation, which was assumed to be largely unregulated prior to the pioneering studies of Avram Hershko, Aaron Ciechanover and Irwin Rose [45]. Indeed, numerous pieces of the ubiquitin-dependent pathway of protein degradation were known, but not recognized as such [46], [47], [48], [49].